P13.15 Pre-clinical trial of T601 oncolytic virus for high grade glima via intra-tumoral injection

BACKGROUND An effective therapeutic method still hasn’t been devised for lethal high grade glioma. Thus, a method with high anti-tumoral efficiency, tumoral targeting, and acceptable side effect needs to be designed. Oncolytic virotherapy which can specifically lyse tumor cells via mass replication and deleting nucleotide metabolism related gene, like TK, required in viral replication and overexpressed in tumor cells, provides hope for patients. However, the virus only contained TK deletion is unable to show sufficient specificity of anti-tumoral response in tumor cells. Here, the adapted strain of vaccinia virus with high tumoral specificity due to TK and RR deletion and FUC1 insertion, named T601, is chosen in this project. In clinical application, intra-tumoral injection showed improved anti-tumoral efficiency and acceptable side effect. However, intra-tumoral viral injection in orthotropic glioma model is rare. In this project, various biosafety and antitumoral efficiency parameter would be tested for confirming the biosafety and reliability of intra-tumoral T601 viral injection for future clinical trials. MATERIAL AND METHODS For measuring the IC50 of T601, 10 different amounts of virus was tested in vitro via calculating cell viability with CCK-8(cell counting kit-8). For measuring the further antitumoral response of FCU1, different concentration of the 5-FC was added into the medium with IC50 viral amount. To ensure the biosafety of T601, MTD (maximum tolerance dose) was measured. Based on the MTD result, for evaluating the anti-tumoral efficiency, 106 pfu,105 pfu,104 pfu of virus was intra-tumoral injected in orthotopic GBM bearing mice. Tumor size was measured once a week through in vivo bioimaging system. RESULTS 0.022 MOI, the IC50 of T601, showed high cytotoxicity of T601. Moreover, the significantly decreased cell viability under the combined treatment of 5-FC and 0.22MOI T601 showed intact anti-tumoral function. In MTD assay, except for 107 group, no significant weight loss was found. However, in 107 pfu group, mean body weight decreased around 10% and animal fatality happened on day 9. According to the MTD result, certain amount of virus was intra-tumorally injected. In all treatment group, the tumor size was significantly shrined. At the same time, the survival rate of mice under viral treatment was significantly extended. CONCLUSION In summary, T601 exhibited efficient anti-tumoral function and acceptable side effect. T601 treatment prolonged the survival period of GBM mice with acceptable neurotoxicity, demonstrating that T601 contains necessary criterial for intra-tumoral injection. Ultimately, this project provided basic reference information of dose for future clinical trial.

Focal Ablation Therapies in Prostate Cancer

Focal ablation therapies in prostate cancer have been actively evaluated in the light of recent literature. According to published data,focal ablation therapies appear to be well tolerated and have an acceptable side effect profile. Moreover, while clinical outcomes were not homogenous, short-term oncological results of some focal ablation therapies such as laser and irreversible electroporation (IRE) have been found as good as curative ones. While waiting long-term oncological results, focal ablation therapies in prostate cancer are beinmg used increasingly.

Patterns and prognostic markers for treatment response in generalized epilepsies

ObjectiveTo determine the pattern of treatment response in patients with idiopathic generalized epilepsy (IGE) and whether routinely assessed clinical and neurophysiological parameters allow predicting response to lamotrigine, levetiracetam, or valproic acid.MethodsIn 328 adult patients with IGE, demographic data, imaging, EEG data, current and prior antiepileptic treatment, treatment outcome, and side effects were analyzed from the patients' medical files and patient interviews.ResultsSeizure freedom with acceptable side effects at the first attempt was achieved in 61 (18.6%) patients. One hundred four (31.7%) patients tried ≥3 antiepileptic drugs before achieving seizure control at the last follow-up. Lamotrigine, levetiracetam, and valproic acid showed differential response rates (39.8% vs 47.5% vs 71.1%) that were most pronounced in patients with juvenile myoclonic epilepsy. The risk of having side effects was higher with valproic acid (23.7%) than with lamotrigine (10.4%) or levetiracetam (20.4%) treatment, contributing to the low retention rate of valproic acid (53.7%). Treatment resistance was associated with established risk factors. Multivariate analyses aiming at identifying clinical indicators for response to specific drugs did not reveal putative biomarkers when corrected for drug resistance.ConclusionDespite a high rate of seizure control, the chance of achieving seizure control and acceptable side effects at first attempt was low due to an inverse association of effectiveness and side effects of the 3 most commonly used drugs. Routinely assessed clinical parameters were not indicative for response to specific drugs.Classification of evidenceThis study provides Class II evidence that for patients with IGE, various clinical factors do not predict a response to specific antiepileptic drugs.

Patient controlled analgesia (PCA) vs non-PCA intravenous hydromorphone titration for severe cancer pain: A multi-center, phase III trial, HMORCT09-1.

12078 Background: The titration of opioid dosage is necessary for adequate pain relief with acceptable side effects among individuals with cancer pain. The titration process can be achieved by non-patient administration or PCA pump. The aim of this study was to evaluate the efficacy of PCA versus non-PAC titration for severe cancer pain. Methods: Patients with severe cancer pain (NRS ≥ 7/10 at rest) were randomized into PCA or non-PCA titration and stratified by opioid tolerance or intolerance. For PCA, the pump was set as no continuous dose, hydromorphone bolus dose was 10%-20% of the total equianalgesic of past 24h for opioid tolerance, or 0.5 mg for opioid intolerance. The lockout time was 15 min. For non-PCA, initial hydromorphone bolus was the same with PCA. Reassess pain at 15 min. The dose of hydromorphone was increased by 50%-100% if pain unchanged or increased, or repeated if NRS was 4-6, or continue at current dose as needed if NRS≤3. The primary endpoint was the time to successful titration (TST) - time from start to the time of pain controlled at NRS ≤ 3 in two consecutive evaluation with 15-min intervals, which was tested by K-M curve. Results: A total of 214 patients were randomized (106 in PCA, 108 in non-PCA) in 17 study sites. The most common sites of primary cancer were lung (21.03%), stomach (15.89%), colorectal (14.49%) etc. Median TSTs were 0.50h in PCA, 0.79h in non-PCA, HR 1.64 (95% CI 1.23, 2.17, P = 0.00127). In opioid tolerance, 0.50h in PCA, 1.00h in non-PCA (HR 1.92, 95% CI 1.32, 2.78, P = 0.0025). while in opioid intolerance, 0.50h in PCA and 0.50 in non-PCA (HR 1.35, 95% CI 0.88, 2.04, P = 0.162). The median dosage of hydromorphone for TST was 1.00mg (P25, P75 0.50, 2.00) in PCA, 1.50mg (P25, P75 1.00, 2.50) in non-PCA (P = 0.086). In opioid tolerance, 1.00mg (P25, P75 1.00, 2.00) in PCA, 2.00mg (P25, P75 1.00, 4.00) in non-PCA (P = 0.009). In opioid intolerance, 1.00mg (P25, P75 0.50, 2.00) in PCA and 1.00 mg (P25, P75 0.50, 2.00) non-PCA (P = 0.793). Mean patient satisfaction assessed by ESAS score was significantly superior in PCA to non-PCA (0.62±0.67 vs 1.27±0.98 for ITT, 0.66±0.66 vs 1.39±1.00 for opioid tolerance, and 0.56±0.69 vs 1.13±0.95 for opioid intolerance). Adverse events were similar in both PCA/non-PCA groups. Conclusions: PCA IV hydromorphone titration provided quicker analgesic effect, higher patients satisfaction, and a similar tolerability as compared to non-PCA administration in patients with severe cancer pain. Clinical trial information: NCT03375515 .

GMI-1271, a novel E-selectin antagonist, combined with induction chemotherapy in elderly patients with untreated AML.

2560 Background: The outcomes for elderly patients (pts) with acute myeloid leukemia (AML) remain poor, therefore newer and less toxic therapies are urgently needed. The binding of E-selectin (E-sel), an adhesion molecule expressed in the bone marrow, to the leukemic cell surface activates survival pathways and promotes chemotherapy resistance. GMI-1271, a novel E-sel antagonist, enhances chemotherapy responses and protects from common toxicities in preclinical models (Becker ASH 2013; Winkler ASH 2013 and 2014). We report interim Phase 2 data for GMI-1271 plus chemotherapy in elderly untreated pts with AML. Methods: Pts ≥ 60 yrs with untreated AML, ECOG 0-2, and adequate renal and hepatic function were eligible. Prior treatment of MDS was allowed. GMI-1271 (10 mg/kg) was given 24 hrs prior, during and 48 hrs post induction with infusional cytarabine and idarubicin (7+3). Safety, tolerability, and anti-leukemia activity were assessed. Two cycles of induction were allowed and responders could receive consolidation with GMI-1271 plus intermediate dose cytarabine. Dose-limiting toxicity (DLT), defined as myelosuppression in the absence of disease or related Grade 3 (Gr) non-hematologic toxicity beyond day 42, was assessed in the first 3 pts. Results: 24 pts have been enrolled to date and 17 are evaluable for response. The median age was 68 years (range, 60-79) with 58% male pts, 50% secondary AML (sAML) pts and 25% with high-risk cytogenetics (by SWOG). The first 3 pts had no DLT, allowing enrollment to proceed. Common Gr 3/4 AEs included febrile neutropenia (47%), pneumonia (20%), pulmonary edema (13%) and non-fatal respiratory failure (13%). 2 pts died of sepsis within 60 days. The remission rate (CR/CRi) was 12/17 (71%). CR/CRi rate was 75% for pts with de novodisease and 67% for pts with sAML. E-sel ligand was expressed at high levels on blasts in the majority of pts. Conclusions: The addition of GMI-1271 to anthracycline-based induction chemotherapy in untreated elderly pts with AML demonstrates a high remission rate with acceptable side effect profile and low induction mortality. This study compares favorably to previous studies (Lancet, ASCO 2016). A randomized trial is being planned. Clinical trial information: NCT02306291.

The efficacy of colchicine and dapsone combination therapy in relapsed immune thrombocytopenia

The aim of the present paper is to evaluate the efficacy and safety of colchicine and dapsone combination therapy in cases of steroid-dependent, relapsed and refractory immune thrombocytopenia (ITP). This is a retrospective study of ITP patients who attended the Hematology Clinic at Chiang Mai University Hospital (Thailand) from 1 January 2008 to 30 September 2014. Medical records and clinical data were reviewed for efficacy and adverse effects. Sixty-four ITP patients received the combination therapy. The median age was 46 years and 70.3% were female. The majority (65.6%) were relapsed ITP patients. Median platelet count before starting treatment was 22.6×109/L. The response rate was 82.8%, with 75.0% of patients having a complete response. Median time to response was 8 weeks. The response rate was higher in relapsed patients (90.4%) compared to refractory (61.5%) and steroid-dependent patients (77.8%). Steroid treatment was discontinued in 30 patients (50%) following combination therapy. The most common side effect was hemolysis due to dapsone which was found in eight patients (12.5%). We can therefore conclude that combination therapy with colchicine and dapsone is an alternative second-line therapy option in relapsed ITP cases with acceptable side effects.

Comparison of Second-Line Quadruple Therapies with or without Bismuth forHelicobacter pyloriInfection

The bismuth-based quadruple regimen has been applied inHelicobacter pylorirescue therapy worldwide. The non-bismuth-based quadruple therapy or “concomitant therapy” is an alternative option in first-line eradication but has not been used in second-line therapy. Discovering a valid regimen for rescue therapy in bismuth-unavailable countries is important. We conducted a randomized controlled trial to compare the efficacies of the standard quadruple therapy and a modified concomitant regimen. One hundred and twenty-four patients were randomly assigned into two groups: RBTM (rabeprozole 20 mg bid., bismuth subcitrate 120 mg qid, tetracycline 500 mg qid, and metronidazole 250 mg qid) and RATM (rabeprozole 20 mg bid., amoxicillin 1 g bid., tetracycline 500 mg qid, and metronidazole 250 mg qid) for 10 days. The eradication rate of the RBTM and RATM regimen was 92.1% and 90.2%, respectively, in intention-to-treat analysis. Patients in both groups had good compliance (~96%). The overall incidence of adverse events was higher in the RATM group (42.6% versus 22.2%,P=0.02), but only seven patients (11.5%) experienced grades 2-3 events. In conclusion, both regimens had good efficacy, compliance, and acceptable side effects. The 10-day RATM treatment could be an alternative rescue therapy in bismuth-unavailable countries.